Many of the procedures presently conducted in the field of nuclear medicine involve radiopharmaceuticals which provide diagnostic images of bloo flow (perfusion) in the major organs and in tumors. The regional uptake of these radiopharmaceuticals within the organ of interest is proportional to flow; high flow regions will display the highest concentration of radiopharmaceutical, while regions of little or no flow have relatively low concentrations. Diagnostic images showing these regiona differences are useful in identifying areas of poor perfusion, but do not provide metabolic information of the state of the tissue within the region of apparently low perfusion.
There is a need for new radiopharmaceuticals which specifically localize in hypoxic tissue, i.e., tissue which is deficient in oxygen, but still viable. These compounds should be retained in regions which are hypoxic, but should not be retained in regions which are normoxic. A radiopharmaceutical with these properties will display relatively high concentrations in such hypoxic regions, with low concentrations in normoxic and infarcted regions. Diagnostic images with this radiopharmaceutical should readily allow the identification of tissue which is at risk of progressing to infarction, but still salvagable in, for example, the heart and brain.
It is well known that tumors often have regions within their mass which are hypoxic. These result when the rapid growth of the tumor is not matched by the extension of tumor vasculature. A radiopharmaceutical which localizes preferentially within regions of hypoxia could also be used to provide images which are useful in the diagnosis and management of therapy of tumors as suggested by Chapman, “Measurement of Tumor Hypoxia by Invasive and Non-Invasive Procedures—A Review of Recent Clinical Studies”, Radiother. Oncol., 20(S1), 13-19 (1991). Additionally, a compound which localizes within the hypoxic region of tumors, but is labeled with a radionuclide with suitable α- or β-emissions could be us d for the internal radiotherapy of tumors.
As reported by Martin at al. (“Enhanced Binding of the Hypoxic eli Marker [3H] Fluoromisonidazole”, J. Nucl. Med., Vol. 30, No. 2, 194-201 (1989)) an Hoffman et al. (“Binding of the Hypoxic Tracer [H-3] Misonidazole in Cerebral Ischemia”, Stroke, Vol. 18, 168 (1987)), hypoxia-localizing moieties, for example, hypoxia-mediated nitroheterocyclic compounds (e.g., nitroimidazoles and derivatives thereof) are known to be retained in hypoxic tissue. In the brain or heart, hypoxia typically follows ischemic episodes produced by, for example, arterial occlusions or by a combination of increased demand and insufficient flow. Additionally, Kob et al., (“Hypoxia Imaging of Tumors Using [F-18] Fluoronitroimidazole”, J. Nucl. Med., Vol. 30, 789 (1989) have attempted diagnostic imaging of tumors using a nitroimidazole radiolabeled with 18F. A nitroimidazole labeled with 123I has been proposed by Biskupiak et al. (“Synthesis of an (iodovinyl)misonidazole derivative for hypoxia imaging”, J. Med. Chem., Vol. 34, No. 7, 2165-2168 (1991)) as a radiopharmaceutical suitable for use with single-photon imaging equipment.
While the precise mechanism for retention of hypoxia-localizin compounds is not known, it is believed that nitroheteroaromatic compounds, such as misonidazole, undergo intracellular enzymatic reduction (for example, J. D. Chapman “The Detection and Measurement of Hypoxic Cells in Tumors”, Cancer, Vol. 54, 2441-2449 (1984)). This process is believed to be reversible in cells with a normal oxygen artial pressure, but in cells which are deficient in oxygen, further reduction can take place. This leads to the formation of reactive species which bind to or are trapped as intracellular components, providing for preferential entrapment in hypoxic cells. It is necessary, therefore, for hypoxia imaging compounds to possess certain specific properties; they must be able to traverse cell membranes, and they must be capable of being reduced, for example, by reductases such as xanthine oxidase.
The hypoxia imaging agents mentioned above are less than ideal for routine clinical use. For example, the positron-emitting isotopes (such as 18F) a e cyclotron-produced and short-lived, thus requiring that isotope production, radiochemical synthesis, and diagnostic imaging be performed at a single site or region. The cost of procedures based on positron-emitting isotopes are very high, and there are very fe of these centers worldwide. While 123I-radiopharmaceuticals may be used with widely-vailable gamma camera imaging systems, 123I has a 13 hour half-life (which restricts the istribution of radiopharmaceuticals based on this isotope) and is expensive to produce. Nitroimidazoles labeled with 3H are not suitable for in vivo clinical imaging and can be used for basic research studies only.
The preferred radioisotope for medical imaging is 99mTc. Its 140 keV γ-photon is ideal for use with widely-available gamma cameras. It has a short (6 hour) half life, which is desirable when considering patient dosimetry. 99mTc is readily available at relatively low cost through commercially-produced 99Mo/99mTc generator systems. As a result, over 80% of all radionuclide imaging studies conducted worldwide utilize this radioisotope. To permit widespread use of a radiopharmaceutical for hypoxia imaging, it is necessary that the compound be labeled with 99mTc. For radiotherapy, the rhenium radioisotopes, particularly 186Re and 188Re, have demonstrated utility.
EP 411,491 discloses boronic acid adducts of rhenium dioxime and technetium-99m dioxime complexes linked to various nitroimidazoles. Although these complexes are believed to be useful for diagnostic and therapeutic purposes, it would be desirable to obtain higher levels of the rhenium or technetium radionuclide in the targeted area, than are achieved with this class of capped-dioxime nitroimidazole complexes. It was demonstrated that the compounds disclosed in EP 411,491 possess reduction potentials similar to 2-nitroimidazole derivatives known to localize in hypoxic regions. In addition, the reduction of these compounds is catalyzed by xanthine oxidase. However, these compounds have poor membrane permeability. Thus, while these compounds might be retained by hypoxic cells, delivery of these compounds to the intracellular domain of these cells may be less than ideal. In addition, the complexes described in EP 411,491 require a heating step to form the hypoxialocalizing radiolabeled compounds. It would be more convenient for the routine use of such hypoxia-localizing radiolabeled compounds to be able to prepare such complexes at ambient temperatures.
Radiolabeled complexes of hypoxia-localizing moieties which retain the biochemical behavior and affinity of such moieties, which are labeled at room temperature with a suitable, easy-to-use radionuclide, and which are capable of providing increased amounts of the desired radionuclide to the targeted area, would be a useful addition to the art.